The long-term goal is to understand physicochemical and chemical-biological interactions in a metal-working fluid (MWF) formulation in order to be able to predict quantitatively how these formulations influence dermal absorption of industrial biocides used as additives in these chemically complex formulations. Current dermal risk assessments only evaluate dermal absorption of single chemicals which has limited use in occupational exposure to chemically complex MWF formulations. The primary objective of this research project is to utilize the membrane-coated fibers (MCF) to characterize the distribution behavior between a defined MWF formulation, a MWF biocide, and an inert membrane and to relate this phase distribution to solvation parameters within a linear solvation energy relationship (LSER) framework that is also applicable to dermal permeability. The central hypothesis to be tested is that the presence of MWF formulations will alter the phase distribution of biocides between the formulation and the MCF and/or skin. These changes in biocide distribution can be expressed in terms of interaction coefficients ( values) that can be used in future extrapolations to a defined formulation scenario and thus can be of value to MWF formulators and metal fabrication workers by indicating what formulations are more likely to promote skin penetration and possibly adverse occupational effects. The rationale for this approach is that MWF formulations can modulate biocide partitioning and diffusion by quantifiable physicochemical interactions ( values). The MCF approach within the LSER framework allows for a physicochemical examination of these formulation effects using a multi-fiber MCF array system and validated in porcine skin diffusion cells and finally validated in vivo for systemic absorption. The following three specific aims will be pursued to accomplish the stated objectives: 1) To quantify mixture interactions influencing transport of MWF biocides between MWF formulations and the membrane coated fibers (MCF). This first involves calibration of a diverse series of fibers followed by exposure of a 5-component MCF array to MWF formulations to provide interaction coefficients ( values) for a defined formulation. 2) To quantify chemical-biological interactions in a biological membrane system following exposure to MWF formulations in porcine skin flow-through diffusion cell. Dermal in vitro experiments will calibrate permeability in the biological system and validate formulation interaction coefficients in the MCF array for the biocides. 3) To quantify the effect of MWF formulations on the in vivo dermal absorption of MWF biocides. This involves comparative analysis of interaction coefficients between the MCF array and the two biological systems (in vitro and in vivo) and will validate the proposed MCF- array approach within the LSER framework to predict the dermal permeability of occupationally relevant toxicants such as MWF biocides in a defined in MWF formulations. PUBLIC HEALTH RELEVANCE: Workers in the metal fabrication industry are more often exposed to metal working fluids (MWF) and its components such as biocides via the skin that can cause harm to the skin and/or the entire body if absorbed by the dermal route. Many of these workers are exposed to more than one chemical additive in any given MWF formulation, and there is little or no means of estimating what class of MWF formulations can result in increased or decreased absorption of biocides across skin. Our proposal describes a novel technique that models biocide absorption in skin on the basis of quantitative changes in physicochemical properties associated with the formulation interacting with a model membrane and then validated in skin in vitro and in vivo to determine validity of these models in an occupational dermal exposure. Ultimately, the products of this research will help inform the development and risk assessment of formulations that afford greater protection.